1. Field of the Invention
The present invention relates to a process for the production of N-formyl-L-.alpha.-aspartyl-L-phenylalanine or its methyl ester, which is useful as an intermediate for the preparation of a dipeptide sweetener, N-.alpha.-aspartyl-L-phenylalanine methyl ester. More particularly, it relates to a process for the production of said intermediate, which comprises reacting aspartic acid with approximately stoichiometric quantities of formic acid and acetic anhydride in the presence of or in the absence of a catalyst, such as a metal oxide, a metal hydroxide or a salt thereof, to form N-formyl-aspartic anhydride, and then directly adding to the resulting reaction mixture phenylalanine or its methyl ester, so as to allow the two compounds to condense.
2. Description of the Related Art
L-.alpha.-aspartyl-L-phenylalanine methyl ester is known to be a low caloric sweetener with a strong taste very similar to that of sucrose.
In the hitherto known processes, the dipeptide ester has been prepared, for example, by reacting an N-protected-L-aspartic anhydride with an L-phenylalanine methyl ester in a solvent, followed by the elimination of the protective group (see U.S. Pat. No. 3,786,039); or by reacting an N-protected-L-aspartic anhydride with L-phenylalanine and then eliminating the protective group to give L-.alpha.-aspartyl-L-phenylalanine, followed by esterification (see Japanese Patent Publication No. 26,133/80 and U.S. Pat. No. 3,933,781). It is preferable, from an economic point of view, to use a formyl group for the protection of the amino group in any of the above processes. In cases where N-formyl-L-aspartyl anhydride is allowed to condense with L-phenylalanine or its methyl ester to obtain L-.alpha.-aspartyl-L-phenylalanine methyl ester, usually N-formyl-L-aspartic anhydride purified from a dehydration reaction medium must be used, resulting in practical problems. N-formyl-L-aspartic anhydride is usually produced by adding L-aspartic acid to a large excess of formic acid and acetic anhydride. In this case, a large quantity of formic acid remains in the reaction mixture even after the completion of the reaction. The formic acid not only impedes the condensation of the N-formyl-L-aspartic anhydride but also decreases the ratio of the desired N-formyl-L-.alpha.-aspartyl-L-phenylalanine (.alpha.-isomer) or its methyl ester to N-formyl-L-.beta.-aspartyl-L-phenylalanine (.beta.-isomer) or its methyl ester. Because of this, the N-formyl-L-aspartic anhydride must be separated from the reaction medium containing the residual formic acid, for example, by adding aromatic hydrocarbons and/or halogenated hydrocarbons to the reaction (dehydration) mixture to precipitate crystals of the anhydride (see Japanese Patent Application Laid-Open No. 91,210/76) or by allowing the reaction mixture to evaporate to dryness (see U.S. Pat. No. 3,933,781). It would be obvious to those skilled in the art that the same effect can be attained by continuous or all at once addition of a large quantity of acetic acid or aromatic hydrocarbons to the reaction mixture and then evaporating off the residual formic acid.
From an industrial viewpoint, the known processes are disadvantageous in that a large quantity of energy is required for cooling, separation or evaporation and such processes become complicated with respect to plant investment.
In addition to complication of the main processes, there is also the disadvantage that a fractionating plant must be constructed and operated for the recovery and reuse of each component from the mixture with formic acid and acetic acid or the mixture with formic acid, acetic acid and aromatic hydrocarbons, separated out of the reaction medium.
A process for producing N-formyl-L-aspartic anhydride has also been proposed in which formic acid and acetic acid are used in stoichiometric quantities with respect to L-aspartic acid (see Japanese Patent Application Laid-Open No. 46,279/84). However, this process also has a problem when applied to the synthesis of N-formyl-L-.alpha.-aspartyl-L-phenylalanine or its methyl ester (N-formyl-.alpha.-dipeptide) involving condensation with L-phenylalanine or its methyl ester. To be more specific, a long period of time (up to a hundred hours or more) is required for the dehydration, and the yield of N-formyl-L-aspartic anhydride based on the starting material, i.e., L-aspartic acid, is lower than in the process utilizing an excess of formic acid. Consequently, the process results in an increase in the amount of impurities, including unreacted starting materials, and requires separation of the crystals of the anhydride. It is therefore apparent that this process does not overcome the disadvantage in the process utilizing an excess of formic acid. In addition, this process is also disadvantageous in that the loss of the anhydride during the process of crystallization causes an apparent decrease in the yield of the N-formyl-.alpha.-dipeptide in the condensation step, calculated on the basis of the starting L-aspartic acid.
As other known processes for producing N-formyl-L-aspartic anhydride, there is one in which a fine powder of L-aspartic acid is employed (see Japanese Patent Application No. 258,765/84), and one wherein irradiation with ultrasonic waves during dehydration is employed (see Japanese Patent Application Laid-Open No. 137,875/86). It is known that in these processes the dehydration can be completed within a short period of time even when formic acid and acetic anhydride are used in small quantities. However, these processes merely make it possible to shorten the reaction time by means of the addition of such equipment as a pulverizer. In other words, the prior processes for producing N-formyl-L-aspartic anhydride merely intended to produce the anhydride in high purity and in high yield, and no considerations have been paid to its use in the following step to produce the N-formyl-.alpha.-dipeptide. Accordingly, the hitherto known processes were not satisfactory for the purpose of the present invention.
Therefore, a need continues to exist for a new process for production of N-formyl-L-.alpha.-aspartyl-L-phenylalanine or its methyl ester.